In normal pregnancy the mother's immune system is programmed into a profile where humoral immunity is preferred to cell-mediated immunity. Studies on mechanism(s) underlying the preference for antibody production are very few in number although many investigations have addressed the question of how cell-mediated destruction of the placenta and its membranes might be protected from cytotoxic cells. Recently, we uncovered a likely explantation for high antibody production. When investigating synthesis of non-apoptosis-inducing Tumor Necrosis Family ligands/receptors in human placentas, we learned that BAFF, a promoter of B lymphocyte survival, and APRIL, which binds to the same receptors as BAFF but whose mode of action is not well understood, are transcribed and translated in human placentas. Thus, these two ligands may effect the deviation toward production of antibodies. In this study, we propose three Specific Aims. Aim 1 is to define production of BAFF and APRIL in specific subpopulations of human placental cells and identify conditions controlling transcription and translation. We are particularly interested in two cytokines (IFN 7 and IL-10), hypoxia and soluble HLA-G, and provide some preliminary evidence in support of idea that these molecules, which are associated with early pregnancy and preeclampsia, may be modulators of BAFF and/or APRIL gene expression. In Aim 2 we propose to investigate the effects of gene deletion/overexpression on pregnancy in mice. Our preliminary studies show that both BAFF and APRIL are expressed in mouse placentas, and both transgenic and knockout models are available. Aim 3 is designed to identify relationships between pregnancy and serum levels of BAFF and APRIL in mice, healthy women and women with autioimmune disease. The studies on healthy women prior to and during pregnancy will be assessed in collaboration with C. Ober, University of Chicago. Similar sets of sera from women with autoimmune disorders will be collected by Consultants J. L. Nelson and J. Buyon. The patients will be stratified by disorder and their sera analyzed for levels of BAFF and APRIL. We expect these studies to provide new insights into how pregnancy proceeds without compromising maternal defense against pathogens, to provide important new information on mothers with underlying autoimmune disease, and, ultimately, to lead toward new treatment modalities.